Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial.

Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.

Effects of a Communication Intervention Randomized Controlled Trial to Enable Goals-of-Care Discussions.

PURPOSE: Patients with advanced cancer often have a poor understanding of cancer incurability, which correlates with more aggressive treatment near the end of life (EOL). We sought to determine whether training oncologists to elicit patient values for goals-of-care (GoC) discussions will increase and improve these discussions. We explored its impact on use of aggressive care at EOL. METHODS: We enrolled and used block randomization to assign 92% of solid tumor oncologists to 2-hour communication skills training and four coaching sessions. We surveyed 265 patient with newly diagnosed advanced cancer with < 2-year life expectancy at baseline and 6 months. We assessed prevalence and quality of GoC communication, change in communication skills, and use of aggressive care in the last month of life. RESULTS: Intervention (INT) oncologists' (n = 11) skill to elicit patient values increased (27%-55%), while usual care (UC) oncologists' (n = 11) skill did not (9%-0%; P = .01). Forty-eight percent (n = 74) INT v 51% (n = 56) UC patients reported a GoC discussion (P = .61). There was no difference in the prevalence or quality of GoC communication between groups (global odds ratio, 0.84; 95% CI, 0.57 to 1.23). Within 6 months, there was no difference in deaths (18 INT v 16 UC; P = .51), mean hospitalizations (0.47 INT v 0.42 UC; P = .63), intensive care unit admissions (5% INT v 9% UC; P = .65), or chemotherapy (26% INT v 16% UC; P = .39). CONCLUSION: Use of a coaching model focused on teaching oncologists to elicit patient values improved that skill but did not increase prevalence or quality of GoC discussions among patients with advanced cancer. There was no impact on high care utilization at EOL.

Phase II trial of erlotinib and capecitabine for patients with previously untreated metastatic colorectal cancer.

BACKGROUND: This Simon 2-stage phase II trial was designed to document antitumor activity of capecitabine in combination with erlotinib in patients with previously untreated metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Time to tumor progression, objective response rate, and time to treatment failure were to be assessed. Secondary objectives included determination of toxicity. This trial was closed prematurely because of slower-than-expected accrual. Thirteen patients were enrolled, and all are off protocol treatment at the time of this report. RESULTS: Notably, 4 subjects discontinued therapy because of adverse events. Of 10 evaluable patients, 1 attained a complete response, 1 attained a partial response, 3 had stable disease, and 5 had progressive disease. Median time to disease progression was 21 weeks, with a range of 8-85 weeks. Overall survival ranged from 12 weeks to 182 weeks, with a median of 76 weeks. CONCLUSION: The toxicities and challenge to complete accrual observed in this trial are consistent with the experience of others attempting to develop erlotinib as part of combination treatment for advanced CRC.

Treatment of malignant ascites.

OPINION STATEMENT: The management of malignant ascites is a significant challenge in gastrointestinal medical oncology. Current treatment strategies include diuretic therapy, paracentesis, peritoneal drains, and venous shunts. However, there are no established evidence-based guidelines, and there is a lack of randomized controlled trials identifying optimal therapy. Newer therapies are emerging and will need further study. By summarizing published studies, this review is intended to add some clarity to currently available strategies for the management of malignant ascites associated with hepatobiliary cancers. Notably, however, much of the available data for the management of malignant ascites comes from the gynecologic oncology experience, specifically from studies in ovarian cancer. Therefore, successful approaches used in this malignancy may be lead candidates for development in hepatobiliary cancer-associated ascites and are reviewed in this paper.

Management of adult idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP) is defined as isolated thrombocytopenia without a clinically apparent cause. It is categorized as acute, chronic, and refractory. Its clinical presentation ranges from acute to insidious and the bleeding may vary from minimal to severe. The target platelet count with therapy is more than 30,000/microL in sedentary individuals. Since studies regarding therapies for ITP have been mostly uncontrolled case series, the treatment recommendations are largely derived from expert opinion. This review paper summarizes the data on available therapies for adult acute and chronic/refractory ITP. The therapies include splenectomy, steroids, intravenous immunoglobulin, anti-Rh(D), monoclonal antibodies, danazol, chemotherapy, plasma exchange, and others.

Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers.

PURPOSE: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. PATIENTS AND METHODS: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. RESULTS: The starting dose of clofarabine (15 mg/m(2)) was myelosuppressive, requiring several dose de-escalations to 2 mg/m(2), the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m(2), with several escalations to 55 mg/m(2). The DLT was reversible hepatotoxicity at 55 mg/m(2). The recommended dose for acute leukemia phase II studies was 40 mg/m(2). Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m(2), the median plasma clofarabine level was 1.5 micro mol/L (range, 0.42 to 3.2 micro mol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. CONCLUSION: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m(2) for solid tumors, the DLT being myelosuppression; and 40 mg/m(2) for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.

The horizon of antiangiogenic therapy for colorectal cancer.

Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning U.S. Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.

Comparison of cardiac events associated with liposomal doxorubicin, epirubicin and doxorubicin in breast cancer: a Bayesian network meta-analysis.

BACKGROUND: Anthracyclines play a broad and important role in the care of patients with either operable or metastatic breast cancer. However cardiotoxicity narrows the therapeutic index of this drug class leading to potentially clinically meaningful treatment delays or discontinuations. We conducted a Bayesian network meta-analysis, a validated statistical methodology, allowing direct and indirect comparison of cardiotoxicity of different anthracycline and non-anthracycline regimens. METHODS: We conducted a systematic review of prospective randomised controlled trials through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Google Scholar comparing non-anthracycline based regimens (NON), doxorubicin (DOX), epirubicin (EPI) and liposomal doxorubicin (LD). We included studies published up to 1st January 2014 in both adjuvant and metastatic contexts. Notably, HER2/neu-targeted regimens were excluded. We assessed the studies' eligibility criteria and data collection with consensus of two independent authors. Our primary outcome measure was cardiac events grade 3 or greater (CE3) in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. A Bayesian pairwise and network meta-analysis was conducted to estimate pooled Odds Ratio (OR). FINDINGS: Nineteen randomised controlled trials met eligibility criteria and were included in this analysis. We found a trend showing that LD is less cardiotoxic than DOX with an OR of 0.60 (95% confidence interval (CI) 0.34-1.07) There was no difference between Epi and LD with an OR of 0.95 (95%CI 0.39-2.33). DOX is more cardiotoxic than Non with an OR of 1.57 (95%CI 0.90-2.72). INTERPRETATION: DOX has higher CE3 rates than NON does. LD statistically trended to lower cardiac event rates than DOX. Non-statistical significance among EPI, LD and DOX with regard to cardiac toxicity indicates that avoidance of CE3 should not motivate selection of a particular anthracycline in otherwise healthy women in whom total lifetime anthracycline exposure will likely be limited. Overall low incidence of CE3 with any type of anthracycline indicates that we can safely use any anthracycline if cumulative dose limits are not exceeded. While CE3 does not limit our choice of anthracycline LD appears to be the least cardiotoxic. FUNDING: Takeo Fujii is supported by the grant named Young Investigator Award for Study Abroad in Clinical Epidemiology from St. Luke's Life Science Institution.

Gastric Perforation Following Prophylactic Embolization of Right Gastric and Gastroduodenal Arteries Prior to Selective Internal Radiation Therapy.

Prophylactic gastroduodenal artery (GDA) and right gastric artery (RGA) embolization for prevention of gastric ulceration in patients with hepatic metastases from colorectal cancer undergoing Selective Internal Radiation Therapy (SIRT) are relatively safe. Herein, we present a case of gastric perforation following prophylactic embolization of the GDA and RGA for SIRT in a 43-year-old male with sigmoid colon adenocarcinoma and multiple hepatic metastases.

A comprehensive update on the use of chemotherapy for metastatic pancreatic adenocarcinoma.

Phase II trials of combination chemotherapies have shown encouraging palliative benefit, objective response rates, and survival outcomes. Until ongoing phase III trials confirm these benefits, the current standard treatment for metastatic pancreatic adenocarcinoma remains single agent gemcitabine. The fixed rate infusion schedule of 10 mg/m2/min is gaining wide acceptance and is a promising investigational priority. A very reasonable alternative to single agent gemcitabine, and our bias, is enrollment into clinical trials evaluating novel gemcitabine-based combinations. Further investigation is needed to determine optimal incorporation of so-called targeted therapy with combination chemotherapy.

Gallbladder and biliary tract carcinoma: A comprehensive update, Part 2.

Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. These cancers are often diagnosed in an advanced stage due to their nonspecific symptomatology and until recently have been associated with a dismal prognosis. Recent advances in imaging and surgical techniques along with emerging options in palliative chemotherapy have improved the outlook in these cancers. While complete surgical resection remains the only hope of cure in both these cancers, palliative biliary decompression and chemotherapy result in substantial improvement in quality of life. Part 1 of this review, which appeared in last month's issue, provided a relevant and comprehensive update of molecular pathology, imaging modalities, and surgical care. In part 2, we examine palliative care and systemic therapy in gallbladder and biliary tract carcinomas, as well as the use of liver transplantation in the treatment of cholangiocarcinomas. These strategies are of relevance to internists as well as oncologists caring for these patients.

Gallbladder and biliary tract carcinoma: A comprehensive update, Part 1.

Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. These cancers are often diagnosed in an advanced stage due to their nonspecific symptomatology and until recently have been associated with a dismal prognosis. Recent advances in imaging and surgical techniques along with emerging options in palliative chemotherapy have improved the outlook in these cancers. While complete surgical resection remains the only hope of cure in both these cancers, palliative biliary decompression and chemotherapy result in substantial improvement in quality of life. Part 1 of this review provides a relevant and comprehensive update of molecular pathology, imaging modalities, and surgical care. In part 2, which will appear next month, we will review palliative care and systemic therapy in gallbladder and biliary tract carcinomas, as well as the use of liver transplantation in the treatment of cholangiocarcinomas. These strategies are of relevance to internists as well as oncologists caring for these patients.

Phase I study of oxaliplatin in combination with gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in patients with metastatic solid tumors including adenocarcinoma of the pancreas.

PURPOSE: The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen. METHODS: Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m(2) by fixed-dose-rate infusion), irinotecan (120 mg/m(2)), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m(2) according to the escalation schema. Treatment was repeated every 14 days. RESULTS: The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n = 9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m(2). Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2-110 weeks) with median overall survival of 31.5 weeks (7-139 weeks). CONCLUSIONS: G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m(2). The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.

Chemotherapy and other supportive modalities in the palliative setting for pancreatic cancer.

Metastatic pancreatic cancer is a devastating disease with a dismal prognosis. Gemcitabine chemotherapy has been the mainstay of treatment for many years. Efforts to improve survival outcomes with gemcitabine-based combination chemotherapy regimens have been largely disappointing, with the possible exception of the addition of the targeted agent erlotinib. The multi-agent cytotoxic chemotherapy regimen FOLFIRINOX (sequential administration of oxaliplatin immediately followed by leucovorin over 2 hours, and then irinotecan, followed by a bolus dose of 5-fluorouracil, and finally, a 46-hour infusion of 5-fluorouracil) has significantly improved survival compared with gemcitabine alone; however, this regimen can be highly toxic and may need to be reserved for those with an excellent performance status. This article reviews the existing evidence for the management of patients with metastatic pancreatic cancer with chemotherapy with special attention to careful patient selection. The data for chemotherapy combined with targeted therapy are discussed. Additional supportive modalities in the areas of pharmacologic and nutritional support to maximize quality of life are also outlined.

Antiepidermal growth factor receptor monoclonal antibodies: applications in colorectal cancer.

Patients with metastatic colorectal cancer have a poor prognosis and present a challenge to clinicians. The role of the antiepidermal growth factor receptor (EGFR) pathway in tumorogenesis and tumor progression has been well defined. This paper will review the use of anti-EGFR monoclonal antibodies in the treatment of operable, as well as metastatic colorectal cancer both in the setting of KRAS mutation unselected patients and later in KRAS wild-type patients. Active investigations designed to further identify predictive biomarkers that may be potentially druggable are reviewed as well.

Impact of KRAS Mutations on Management of Colorectal Carcinoma.

The epidermal growth factor receptor (EGFR) pathway is a therapeutic target in the management of colorectal cancer (CRC). EGFR antagonists are active in this disease; however, only a subset of patients respond to such therapy. A Kirsten ras sarcoma viral oncogene (KRAS) wild-type (WT) status of the tumor is necessary, but possibly not sufficient, for a response to anti-EGFR monoclonal antibody therapy. Mechanisms of primary resistance to such therapy in patients harboring KRAS WT tumors are discussed. Strategies to overcome resistance to anti-EGFR monoclonal antibody therapy, including novel agents and combinations of novel therapies, are explored. Also, the use of anti-EGFR monoclonal antibodies in the adjuvant and neoadjuvant setting is reviewed.

Colon cancer and the elderly: from screening to treatment in management of GI disease in the elderly.

Colorectal cancer is one of the commonest tumours in the Westernized world affecting mainly the elderly. This neoplasm in older individuals occurs more often in the right colon and grows more rapidly than in the young, often shows a mucinous histology and mismatch repair gene changes. Effective screening permits discovery of colorectal cancer at an early highly treatable stage and allows for detection and removal of premalignant colorectal adenomas. Screening methods that focus on cancer detection use fecal assays for the presence of blood or altered DNA, those for detection of adenomas (and early cancer) use endoscopic or computerised radiologic techniques. Broad use of screening methods has lowered colorectal cancer development by about 50%. In addition, prevention of the earliest stage of colon carcinogenesis has been shown to be effective in small prospective studies and epidemiologic surveys but have not been employed in the general population. Since 1996 the chemotherapeutic armamentarium for metastatic colorectal cancer has grown beyond 5-fluorouracil to include an oral 5-fluorouracil prodrug, capecitabine as well as irinotecan and oxaliplatin. Three targeted monoclonal antibodies (Moabs), bevacizumab (an anti-vascular endothelial growth factor Moab) and cetuximab/panitumumab, both anti-epidermal growth factor receptor inhibitors, have also earned regulatory approval. Most stage IV patients are treated with all of these drugs over 2 or 3 sequential lines of palliative chemotherapy and attain median survivals approaching 24 months. Lastly, adjuvant oxaliplatin plus 5-fluorouracil for high risk resected stage II and stage III colon cancer patient has led to substantial improvement in cure rates. With appropriate care of age associated comorbidities these treatment modalities are feasible and effective in the geriatric population.

Metastatic pancreatic cancer 2008: is the glass less empty?

Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis, an often fulminant clinical course, and the lack of adequate systemic therapies. Unfortunately, only 5%-25% of patients present with tumors amenable to resection. The median disease-free survival interval following resection for operable pancreatic cancer is 13.4 months for patients treated with adjuvant gemcitabine and 6.9 months for untreated patients. A much higher percentage of patients present with metastatic disease (40%-45%) or locally advanced disease (40%), and have median survival times of 3-6 months or 8-12 months, respectively. The frustrating lack of significant clinical advancements in the treatment of metastatic pancreatic cancer remains one of medical oncology's biggest disappointments. The past decade-long frustration has resulted in regulators, investigators, and practicing oncologists gradually lowering their standards/expectations with regard to interpreting clinical trials. Two of the more important examples of this include the approval of gemcitabine plus erlotinib and the use of a progression-free survival advantage to defend the use of gemcitabine plus oxaliplatin. Given the marginal benefit of systemic antineoplastics, a scholarly review inclusive of other palliative strategies will help oncologists optimize the care of pancreatic cancer patients. This article examines the existing evidence in support of a role for palliative therapy in metastatic pancreatic cancer, describes recent developments with newer chemotherapeutic and molecular-targeted agents, and explores future study designs.

Bortezomib with or without irinotecan in relapsed or refractory colorectal cancer: results from a randomized phase II study.

PURPOSE: To evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC). PATIENTS AND METHODS: Patients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m(2) (arm A) or bortezomib 1.3 mg/m(2) plus irinotecan 125 mg/m(2) (arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability. RESULTS: A preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade >or= 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B. CONCLUSION: Bortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.